Direct anti-metastatic efficacy by the DNA enzyme Dz13 and downregulated MMP-2, MMP-9 and MT1-MMP in tumours

Dz13 is a DNA enzyme designed originally to reduce intimal thickening in injured rat carotid arteries [1]. Since then, this particular 'gene shear' molecule has been shown to have potential therapeutic effects against a variety of disorders as mentioned below. DNAzymes are synthetic, single-stranded DNA-based catalysts engineered to bind to their complementary sequence in a target messenger RNA (mRNA) through Watson-Crick rules for base-pairing and cleave the mRNA at predetermined phosphodiester linkages (reviewed in [2]). For example, Dz13 cleaves the target human c-Jun mRNA at position G1311[1]. By way of a handful of critical studies, these biocatalytic molecules have emerged as a potential new class of nucleic acid-based drugs because of several beneficial attributes [2].Dz13 has been shown in ectopic mouse tumour models to reduce the growth of melanoma indirectly via anti-angiogenesis [3], while exhibiting direct activity against squamous cell carcinoma [4], osteosarcoma, OS [5,6] and liposarcoma [7]. In OS, this agent can be combined with a frontline drug such as doxorubicin for better efficacy [8], especially once it has been administered in a nanoencapsulated form [9]. While Dz13 has direct anti-tumour effects based on reduced cell growth and heightened cell death, the underlying mechanisms have not been elucidated.The proteolytic breakdown of proteins of the extracellular matrix (ECM) has long been recognized as a hallmark of invading primary cancer lesions [10]. Several classes of proteases contribute to ECM breakdown and remodeling, most of which are upregulated in the course of metastatic cancer progression in different types of cancers [11]. Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent endopeptidases that have been studied in the past few decades in the context of cancer, and the consensus view at present is that the main role of MMPs in angiogenesis, tumour growth and metastasis is degradation of ECM and release and/or activat